scholarly journals Sterilizing Activity of Novel TMC207- and PA-824-Containing Regimens in a Murine Model of Tuberculosis

2011 ◽  
Vol 55 (12) ◽  
pp. 5485-5492 ◽  
Author(s):  
Rokeya Tasneen ◽  
Si-Yang Li ◽  
Charles A. Peloquin ◽  
Dinesh Taylor ◽  
Kathy N. Williams ◽  
...  
Keyword(s):  
Murine Model ◽  
Building Blocks ◽  
Drug Combinations ◽  
New Drugs ◽  
Drug Resistant ◽  
First Line ◽  
Duration Of Treatment ◽  
Resistant Tuberculosis ◽  
Novel Drug

ABSTRACTTo truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.

scholarly journals Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis

2012 ◽  
Vol 56 (6) ◽  
pp. 3114-3120 ◽  
Author(s):  
Kathy Williams ◽  
Austin Minkowski ◽  
Opokua Amoabeng ◽  
Charles A. Peloquin ◽  
Dinesh Taylor ◽  
...  
Keyword(s):  
Murine Model ◽  
Rank Order ◽  
Building Blocks ◽  
Drug Combinations ◽  
New Drugs ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis

ABSTRACTNovel oral regimens composed of new drugs with potent activity againstMycobacterium tuberculosisand no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

scholarly journals Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2621-2625 ◽  
Author(s):  
Eric Nuermberger ◽  
Ian Rosenthal ◽  
Sandeep Tyagi ◽  
Kathy N. Williams ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
First Line ◽  
Duration Of Treatment ◽  
Standard Regimen ◽  
Drug Candidates ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Lower Lung ◽  
Tuberculosis Therapy

ABSTRACT The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

scholarly journals New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis

2018 ◽  
Vol 44 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Denise Rossato Silva ◽  
Margareth Dalcolmo ◽  
Simon Tiberi ◽  
Marcos Abdo Arbex ◽  
Marcela Munoz-Torrico ◽  
...  
Keyword(s):  
New Drugs ◽  
Special Focus ◽  
Drug Resistant ◽  
Success Rates ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Repurposed Drugs

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the “white plague”, and promising results are being reported.

scholarly journals Mesenchymal stem cells in tuberculosis therapy

2021 ◽  
Vol 23 (9) ◽  
pp. 462-465
Author(s):  
Anna N. Remezova ◽  
◽  
Anna A. Gorelova ◽  
Anna A. Gorelova ◽  
Alexander N. Muraviev ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cellular Therapy ◽  
Great Promise ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Obligate Intracellular ◽  
Resistant Tuberculosis ◽  
Tuberculosis Therapy

Tuberculosis, caused by the obligate intracellular microorganism Mycobacterium tuberculosis, is one of the oldest known infectious diseases in humans. Modern therapy of tuberculosis, consisting of several antibacterial drugs, is long-term, toxic and requires high compliance from the patient, therefore, the development of new therapeutic strategies that would minimize the duration of treatment and prevent the formation of drug-resistant forms of mycobacteria is relevant and important. Cellular therapy now holds the promise of potential complementary therapeutic options for the treatment of drug-resistant tuberculosis. In recent years, the possibilities of using mesenchymal stem cells in the treatment of tuberculosis of various localization have been widely studied. The use of such cells in conjunction with standard anti-tuberculosis therapy holds great promise for shortening the duration of treatment and reducing the formation of drug-resistant mycobacteria. This article describes the possibilities of using mesenchymal stem cells in the treatment of tuberculosis in patients, including those with extensive and multidrug resistance, as well as the mechanisms of interaction of mesenchymal stem cells with M. tuberculosis.

scholarly journals Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis

2008 ◽  
Vol 52 (4) ◽  
pp. 1522-1524 ◽  
Author(s):  
Eric Nuermberger ◽  
Sandeep Tyagi ◽  
Rokeya Tasneen ◽  
Kathy N. Williams ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
The Novel ◽  
Clinical Testing ◽  
First Line ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACT PA-824 is a nitroimidazo-oxazine in clinical testing for the treatment of tuberculosis. We report that the novel combination of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and pyrazinamide. If applicable to humans, regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis.

scholarly journals Prevalence of primary drug resistant tuberculosis in a tertiary care hospital, Nepal

2015 ◽  
Vol 4 (4) ◽  
pp. 36-38
Author(s):  
R Khunjeli ◽  
U R Mohsin ◽  
S K Shrestha ◽  
S Adhikari ◽  
B Srivastava ◽  
...  
Keyword(s):  
Armed Forces ◽  
Care Hospital ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
First Line ◽  
Sensitivity Testing ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Resistant Strains ◽  
Primary Drug

 Background & objectives: Tuberculosis is a transmissible disease mainly due to inhalation of infected droplet nuclei. The burden of drug resistant tuberculosis is very high in our neighboring countries India and China. Prevalence of primary drug resistant disease is difficult to estimate in our country because culture and sensitivity is not done routinely. This study was an attempt to find out the prevalence of drug resistant in newly diagnosed tuberculosis patients serving in the Nepalese Armed Forces. Methodology: Medical records of patients serving in the Nepalese Armed Forces who had the provisional diagnosis of pulmonary tuberculosis for the first time from July 2012 to June 2014 were analyzed. They had their sputum subjected for both smear and culture with sensitivity testing. Out of 134 patients, 62 had culture positive for Mycobacterium tuberculosis and drug sensitivity was done for the first line 4 antitubercular drugs. Results: Drug resistant strains were found in 5 cases (8.1%) of which 2 (3.2%) were resistant to 4 first line drugs - rifampicin, isoniazid, ethambutol and streptomycin. Prevalence of isoniazid resistance was the highest, found in 3 cases (4.8%). Conclusion: Primary drug resistant tuberculosis in newly diagnosed cases was high even in young healthy adults, and isoniazid resistant strains were the commonest.DOI: http://dx.doi.org/10.3126/jcmc.v4i4.11970

New drugs for hypertension – variations on old themes

1991 ◽  
Vol 29 (6) ◽  
pp. 21-22
Keyword(s):  
Calcium Antagonists ◽  
Plasma Lipids ◽  
Arterial Disease ◽  
New Drugs ◽  
Converting Enzyme ◽  
First Line ◽  
Treatment Of Hypertension ◽  
Adrenergic Blockers ◽  
The Impact

Alpha-adrenergic blockers, calcium antagonists and some angiotensin-converting enzyme (ACE) inhibitors are now promoted as first-line drugs for the treatment of hypertension, competing with the traditional choices of β-adrenergic blockers and diuretics. The older drugs have established long-term benefits, but have some theoretical disadvantages and sometimes unwanted effects. No trials have looked at the impact of these new drugs on cardiovascular disease; studies of their efficacy have examined only immediate outcome measures such as blood pressure, and their effects on other risk factors for arterial disease such as plasma lipids. Choosing a drug for the initial treatment of hypertension has therefore become more difficult. We discuss here a new α-blocker and three recently marketed calcium antagonists.

scholarly journals A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis

2019 ◽  
Vol 55 (1) ◽  
pp. 1901181 ◽  
Author(s):  
Olatunde Olayanju ◽  
Aliasgar Esmail ◽  
Jason Limberis ◽  
Keertan Dheda
Keyword(s):  
Combination Group ◽  
Combination Regimen ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Long Term Outcome ◽  
Prognostic Features ◽  
Resistant Tuberculosis ◽  
Significant Difference ◽  
Pre Treatment

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline–delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline–delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.A bedaquiline–delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.

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